Synthesis and Biological Evaluation of Papain‐Family Cathepsin L‐Like Cysteine Protease Inhibitors Containing a 1,4‐Benzodiazepine Scaffold as Antiprotozoal Agents |
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Authors: | Dr Roberta Ettari Dr Andrea Pinto Dr Lucia Tamborini Dr Ilenia C Angelo Prof Silvana Grasso Prof Maria Zappalà Dr Natale Capodicasa Dr Laura Yzeiraj Dr Esther Gruber Dr Makoah N Aminake Dr Gabriele Pradel Prof Tanja Schirmeister Prof Carlo De?Micheli Prof Paola Conti |
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Affiliation: | 1. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25, 20133 Milano (Italy);2. Dipartimento di Scienze del Farmaco e Prodotti per la Salute, University of Messina, Viale Annunziata, 98168 Messina (Italy);3. Dipartimento di Scienze Chimiche, Università degli Studi di Messina, Via F. Stagno D'Alcontres 31, S. Agata, 98166 Messina (Italy);4. Universiteti “Zoja e K?shillit t? Mir?”, Kompleksi Spitalor Universitar, Rruga Dritan Hoxha, Tirana (Albania);5. Institute of Molecular Biotechnology, RWTH Aachen Unversity, Worringerweg 1, 52074 Aachen (Germany);6. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz (Germany) |
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Abstract: | Novel papain‐family cathepsin L‐like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure–activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzodiazepine ring and the 3‐bromoisoxazoline moiety. Several rhodesain and falcipain‐2 inhibitors displaying single‐digit micromolar or sub‐micromolar antiparasitic activity against one or both parasites were identified, with activities that were one order of magnitude more potent than the model compounds. |
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Keywords: | antiprotozoal agents inhibitors malaria peptidomimetics structure– activity relationships |
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